The MYC oncogene is clearly recognized as an important factor in the pathogenesis of a wide spectrum of cancers. MYC itself, however, is currently an undruggable target. The discovery of alternative strategies to target MYC activity would thus be of immense significance to cancer therapeutics. In recent years, increasing evidence has pointed to the importance of epigenetic protein families in regulating the activities of transcription factors such as MYC and as druggable targets in cancer therapy. We and others have observed amplified MYC signaling in a subset of clear cell renal cell carcinomas (ccRCCs). In this application we propose to identify novel strategies to perturb MYC activity through epigenetic factors and investigate the therapeutic potential of targeting MYC in ccRCCs. We have generated a genetically engineered mouse model of MYC-induced renal tumorigenesis and observed that the viability of the MYC-induced mouse tumors cells in culture is dependent on transgenic MYC expression. In Aim 1, we plan to take advantage of this model system to screen a RNAi library targeting known chromatin regulators. Our goal is to identify siRNAs to epigenetic regulators that inhibit MYC activity and consequently, the viability of MYC-induced mouse renal tumors cells in culture. In Aim 2, we will explore the therapeutic efficacy of targeting MYC activity in RCC patient-derived xenografts (PDXs) enriched for a MYC signature using I- BET151, a bromodomain inhibitor shown to target MYC activity. To this end we propose the following aims: Aim 1: To identify epigenetics factors that play a role in exerting MYC oncogenic function. a) Perform a RNAi screen of the epigenome to identify siRNAs that inhibit the cell viability of MYC-induced mouse primary renal tumors in vitro. b) Validate that the candidates identified in the RNAi screen above inhibit cell viability and MYC activity in vitro. c) Determine whether the knockdown of the candidates identified above by RNAi can inhibit the growth of MYC-induced mouse renal tumors in vivo. Aim 2: To determine the therapeutic potential of I-BET151 on RCCs with high MYC activity using patient derived xenografts (PDXs). a) Revive PDXs in NSG mice and assess MYC activity by qRT-PCR. b) Determine if PDXs with high MYC activity are more sensitive to I-BET151 in vivo.